This application aims to characterize the role of critical tumor suppressor phosphatases in human cancer and exploit the therapeutic potential of a novel type of senescence mechanism that we have discovered to arise In response to their acute inactivation. Deletion, silencing and mutation of the PTEN phosphatase represent one of the most frequent event in human tumorigenesis. INPP4b is a novel tumor suppressor phosphatase that like PTEN, opposes the PI3K pathway, resulting in a consequent hyper-activation of the AKT-mTOR signaling pathway. We believe that this pathway presents an unconventional therapeutic approach to target cancer cells, and ultimately, the therapeutically elusive quiescent cancer stem cell pool. We have reported that acute loss of Pten in vivo stimulates the activation of a potent tumor suppressive cellular senescence pathway, which we have termed PICS (Phosphatase-loss Induced Cellular Senescence) for short. We now have compelling evidence demonstrating that PICS is a unique form of cellular senescence, distinct from both oncogene-induced senescence (OIS) and replicative senescence. The key departure of PICS relative to other senescence mechanisms is characterized by a lack of DNA damage and hyper-replication, thereby refuting the current dogma for senescence induction. Notably, the fact that hyper-replication is dispensable in order to elicit PICS opens up the prospect that pharmacological exploitation of PICS may represent a viable avenue to target the non-proliferative and therapy-evading quiescent cancer initiating cells, in this application we propose to utilize unique mouse models to investigate the in vivo role of Pten and Inpp4b in PICS and tumor suppression; the mechanisms underlying the induction and progression of PICS; its impact on the stem cell populations within the prostate, the efficacy of candidate compounds in the induction of PICS In unique preclinical mouse and human cancer models, and ultimately their ability to be used as anti-cancer agents for chemoprevention and therapy with an emphasis on the eradication of the quiescent cancer stem cell pool. RELEVANCE: This application outlines a program of study to understand the impact of loss of tumor suppressor phosphatases on human cancer. The project focuses on the exciting potential for the development of novel therapies for the treatment of cancer through the targeting of the cancer stem cell.